Although preventable through early detection and modification of risk factors, colorectal cancer (CRC) remains a major public health concern. Early epigenetic alterations and consumption of a low-folate diet have been shown to lead to CRC, possibly due to aberrant DNA methylation. However, the propensity for DNA methylation and its association with gene-diet interactions have not been assessed in a study with prospectively collected dietary information. The overall goal of this proposal is to characterize the association between genetic variation and aberrant DNA methylation of genes in 782 CRC cases in the well-annotated prospective Nurses'Health Study and Health Professionals Follow-up Study. The specific aims are well-powered to evaluate the hypothesis that local DNA sequence context may affect local methylation propensity. These data will enhance our understanding of the association of epigenetic events in colorectal cancer etiology.